title: Cyclin D1 is a major target of miR-206 in cell differentiation and transformation.
abstract: miR-206, a member of the so-called myomiR family, is largely acknowledged as a specific, positive regulator of skeletal muscle differentiation. A growing body of evidence also suggests a tumor suppressor function for miR-206, as it is frequently downregulated in various types of cancers. In this study, we show that miR-206 directly targets cyclin D1 and contributes to the regulation of CCND1 gene expression in both myogenic and non-muscle, transformed cells. We demonstrate that miR-206, either exogenous or endogenous, reduces cyclin D1 levels and proliferation rate in C2C12 cells without promoting differentiation, and that miR-206 knockdown in terminally differentiated C2C12 cells leads to cyclin D1 accumulation in myotubes, indicating that miR-206 might be involved in the maintenance of the post-mitotic state. Targeting of cyclin D1 might also account, at least in part, for the tumor-suppressor activity suggested for miR-206 in previous studies. Accordingly, the analysis of neoplastic and matched normal lung tissues reveals that miR-206 downregulation in lung tumors correlates, in most cases, with higher cyclin D1 levels. Moreover, gain-of-function experiments with cancer-derived cell lines and with in vitro transformed cells indicate that miR-206-mediated cyclin D1 repression is directly coupled to growth inhibition. Altogether, our data highlight a novel activity for miR-206 in skeletal muscle differentiation and identify cyclin D1 as a major target that further strengthens the tumor suppressor function proposed for miR-206.
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin"; Sapienza-Università di Roma; Roma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Alteri
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin"; Sapienza-Università di Roma; Roma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Vito
authors.affiliation: Dipartimento di Bioscienze; Università di Milano; Milano, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Messina
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin"; Sapienza-Università di Roma; Roma, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Pompili
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin"; Sapienza-Università di Roma; Roma, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Calconi
authors.affiliation: Anatomia Patologica; Istituto Nazionale Tumori Regina Elena; Roma, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.affiliation: Anatomia Patologica; Istituto Nazionale Tumori Regina Elena; Roma, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin"; Sapienza-Università di Roma; Roma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Presutti
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin"; Sapienza-Università di Roma; Roma, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Grossi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity
chemical_list: C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D019938:Cyclin D1
keywords: cell proliferation; cell transformation; cyclin D1; miR-206; myogenic differentiation